Fabry disease (FD) is a rare X-linked inherited lysosomal storage disorder in which partial or complete deficiency of α-Galactosidase A (α-Gal) leads to progressive accumulation of metabolic intermediates, particularly globotriaosylceramide in many tissues.1–3
More than 400 mutations for the a-Gal A gene are known.4–6 Hemizygous males carry a defective X-chromosome and develop classical FD, whereas heterozygous females have one normal and one abnormal X chromosome and therefore usually have a later onset of disease than hemizygous males.7–9
Patients with FD usually present in childhood and adolescence with neuropathic pain crises, acroparaesthesia, hypohidrosis, temperature intolerance, gastrointestinal symptoms, angiokeratoma, and corneal abnormalities.10,11 Given the rarity of the disorder and the sometimes non-specific presentation, the diagnosis is often missed and misdiagnosis is common.12 Severe morbidity and mortality follow in adult life due to renal failure, cardiac involvement, and stroke.13 Screening studies on the prevalence of FD in stroke patients (Belgian Fabry Study (BeFaS) and Stroke in young Fabry patients (SIFAP)) revealed a prevalence of 0.5–1% in this population at risk.14,15
Rational of baseline assessment at diagnosis
The diagnosis of FD is made by measuring α-Gal enzymatic activity in lymphocytes in men and mutation analysis of the α-Gal A gene in men and women. Once the diagnosis of FD is confirmed, further investigations to assess of the severity of organ dysfunction is indicated in every patient, in order to select specific and adjunctive therapies and to provide the baseline against which the effectiveness of such therapies will be assessed.16
A specific severity score, such as the Mainz Severity Score Index, allows the medical team to integrate the results of the clinical assessment and additional investigations and allows sequential monitoring of overall disease severity.17
Recommended investigations for FD patients
- Medical history and family pedigree
- Clinical examination
- Vital signs
- Pain score (BPI)
- Age appropriate Quality of Life score (SF-36 or EQ5D)
- Severity Score Index – Mainz Severity Score Index.
- MRI brain examination
- QSART assessment of sweating (where available)
- EMG and quantitative/qualitative sensory testing.
- 24 hour ECG
- Exercise testing
- Blood pressure.
- Glomerular filtration rate/creatinine clearance
- 24 hour urine total protein/microalbumin (or morning sample mg/g creatinine)
- Renal biopsy (at the discretion of the renal physician).
- Slit-lamp examination (cornea verticillata)
- Retro-illumination (cataract)
- Fundoscopy (vascular abnormalities)
- Pure tone audiogram
- Brainstem-evoked potentials – at the discretion of the neurologist
- Vestibular examinations
- Full blood count
- Urea and electrolytes
- Liver function tests
- Fasting lipid profile
- Plasma Gb3/lyso-Gb3
- Urine Gb3/lyso-Gb3
Genetic family screening18
Enzyme replacement therapy
Two enzyme formulations are licensed in Europe by the European Medicines Agency for the treatment of FD: agalsidase alfa (Replagal®, Shire Human Genetic Therapies) at a dose of 0.2mg/kg intravenously over a period of 40 minutes every two weeks; and agalsidase beta (Fabrazyme®, Sanofi-Genzyme Corporation) at a dose of 1mg/kg intravenously over a period of up to four hours every two weeks. Agalsidase beta was approved by the US Food and Drug Administration in 2003.
Agalsidase alfa is produced using a genetically engineered human fibroblast cell line. Agalsidase beta is produced using a Chinese hamster ovary cell line. The product licences are based on the National Institute of Health (NIH) study using agalsidase alfa19 and the trial using agalsidase beta conducted by the Mount Sinai School of Medicine study group.20
Both studies were randomised, double-blind and placebo-controlled. Treatment with algalsidase alfa has also been shown to stabilise renal function, cardiac abnormalities and pain;21,22 to improve quality of life; and to improve hearing.23 Treatment with agalsidase beta has been shown to improve cardiac function24 and renal function.25 A Phase IV randomised double-blind trial of agalsidase beta showed a reduction in clinical progression of the disease in treated patients with respect to renal, cardiac and central nervous system events.26
The safety of enzyme replacement therapy (ERT) in young children has been demonstrated in two clinical trials. A clinical trial of algalsidase alfa in children aged 2–18 years was performed. During the six-month study the drug was well tolerated. The pain scores improved or were unchanged from baseline in 12 of 13 patients. All patients continued on ERT at the end of the clinical trial.17 In the second international, open-label study, children with FD were treated with 1.0 mg/kg agalsidase beta biweekly. ERT was well tolerated; there was superficial dermal capillary GL-3 clearance and gastrointestinal symptoms showed statistically significant improvement.28
Antibody production has been reported with both preparations but there is no clear evidence of any impact on clinical efficacy of treatment.29,30 IgE antibodies are less common and have not been observed in patients receiving agalsidase alfa.
There are no data available on the appropriate starting time of treatment or the group of patients most likely to benefit from therapy. However, because FD is a chronic and progressive disorder, the aim of treatment is to prevent progression, and where disease is already manifest, to try and reverse or stabilise the disease. It is anticipated that treatment will be most successful when started early in the course of the disease. In males, treatment should commence as soon as symptoms of FD appear. In females, the presence of a pathogenic mutation alone is not an indication for ERT; however, criteria for commencing therapy in females should be the same as those in males.31
Indications for initiation of ERT
Treatment with ERT is indicated in patients who have any of the following features shown in Table 1.32
Exclusion criteria for ERT
Exclusion criteria for ERT include:
- The presence of another life-threatening illness with a life expectancy of < one year
- End-stage FD patients who are deemed too severely affected to benefit from ERT (for example, severely incapacitated following cerebrovascular disease).
Adverse events of ERT
Adverse events should be categorised into infusion- and non-infusion-related adverse events and should be scored as mild, moderate or severe. In case of failure to change in symptoms or lack of efficacy, especially deterioration of proteinuria and decline of GFR, the measuring of α-Galactosidase A (neutralising) antibodies may be considered.
Stop criteria for ERT32
- Persistent life threatening or severe infusion reactions that do not respond to prophylaxis
- End-stage renal disease, without an option for renal transplantation, in combination with advanced heart failure
- Lack of response on neuropathic pain.
Pharmacological chaperone ERT
The use of the oral pharmacologic chaperone, migalastat (Galafold®, Amicus), acting as active-site inhibitor, has been shown to promote the refolding and correct trafficking of mutant α-Gal in the presence of residual enzyme activity (amenable mutations-missense mutations).
Galafold is licensed in Europe for the treatment of FD above the age of 16 years based on the data of two Phase III studies:
- 011FACETS: a randomised, placebo-controlled, study of treatment naïve patients with FD and kidney involvement. The primary endpoint, namely the clearance of interstitial capillary GL-3 inclusions, was not reached due to inclusion of 17 patients with a non-amenable mutation in the study.33 However the clinical efficacy of migalastat on the kidney was clearly demonstrated: annualised eGFRCK-D-EPI remained stable over an average of 36 months (Study 011+ extension, n=40). The annualised rate of change over this period was: –0.81 ml/min/1.73 m2/year (95% CI: –2,00–0.37). This long-term effect of migalastat on eGFR is comparable to the decline over time in healthy adults (approximately –1 ml/min/1.73m2) and the decline over time in FD patients treated with agalsidase beta.25
- 012 ATTRACT: a randomised (1.5:1) open-label, active-controlled, study of ERT-treated patients with amenable (responsive) mutations switched to migalastat compared to the control group who remained on ERT of 18 months’ duration. The primary objective of the study was to determine the comparability of migalastat to ERT in their effects on renal function: this primary endpoint was reached. Left ventricular mass index (LVMi) decreased significantly with migalastat treatment while there was no significant change with ERT (secondary endpoint). The composite outcome included cardiac, renal, and cerebrovascular events associated with morbidity and mortality in FD: the proportion of patients who had an event was 29% (10/34) in patients switching from ERT to migalastat and 44% (8/18) in those remaining on ERT.34
Migalastat was generally safe and well-tolerated, as shown in the Phase III studies and extensions.
Adjunctive therapies include treatment of pain, gastrointestinal symptoms, angiokeratoma, primary and/or secondary prevention of organ disease (stroke, renal failure, cardiac disease). These therapies should be available to all patients who are symptomatic.
For adjunctive treatment, there are no randomised controlled trials of these therapies in FD and the evidence for their effectiveness is largely derived from experience in other conditions (Grade C, evidence level IV).
- Chronic pain: anticonvulsants (for example, carbamazepine, gabapentin, topimarate)
- ‘Fabry crises’: non-steroidal anti-inflammatory drugs, opiates, minimisation of activities that trigger painful crisis (for example, temperature changes, physical activity, stress).
- If desired by the patient: removal with argon laser therapy.
- Low-fat diet
- Small and frequent meals
- Motility agents.
Cerebrovascular and cardiovascular disease
- Rigorous control of arterial hypertension, preferably by an ACE inhibitor (avoid β-blockers if sinus bradycardia is present)
- Correct hyperlipidaemia: diet,
- Antithrombotic drugs: aspirin, aspirin + dipyridamole or clopidogrel
- Smoking cessation
- Correct obesity
- Treatment of cardiac arrhythmia: antiarrhythmics, anticoagulants, ICD, pacemaker
- Screening and treatment of coronary and/or carotid insufficiency
- Heart transplantation.
- Proteinuria: ACE inhibitor and ‘sartans’
- Renal failure: dialysis and renal transplantation.
- Neuropsychiatric medication/psychotherapy.
Goals of FD treatment
The goals of FD treatment include an improvement in, or a prevention of deterioration in35:
- Patient subgroup ≥90 and ≤ 135ml/min/1.73m2: GFR decline ≤ 1ml/min/1.73 m2/year
- Patient subgroup <90ml/min/1.73m2: GFR decline ≤2ml/min/1.73m2/year for men and ≤1ml/min/1.73m2/year for women
- Subgroup proteinuria >0.3g/day: no increase in proteinuria
- Subgroup proteinuria ≥1g/day: reduction of proteinuria to <1g/day.
Cardiac structure and function
- Cardiomyopathy (LVMi >51g/m2.7 in men and >48 g/m2.7 in women (LVM indexed to height): reduction of LVM into the normal range
- Improve heart failure
- Reduction in frequency and severity of rhythm disturbances.
- Improve age-appropriate quality of life measurement
- Reduced pain scores
- Reduce incidence of ischaemic stroke
- Normalise growth and development in children.
- Fabry disease (FD) is an X-linked inherited multi-systemic lysosomal storage disease.
- Early diagnosis is essential in order to provide appropriate and timely treatment.
- Awareness of the possibility of this disease must be increased among paediatricians, internal medicine physicians, neurologists, ophthalmologists and ENT specialists.
- FD is a treatable disease, and management is now focused on enzyme replacement therapy, although oral pharmacological chaperone therapy seems a promising alternative treatment for patients with specific mutations. Adjunctive therapies, including antithrombotic agents to prevent stroke and ACE/’sartans’ in case of proteinuria, are also very important in the management of these patients.
- There is a need of collect further outcome survey data (registries) and for comprehensive guidelines for optimising and standardising the diagnosis and treatment of FD patients.
- Brady RO et al. Enzymatic defect in Fabry’s disease. Ceramidetrihexosidase deficiency. N Engl J Med 1967;276:1163–7.
- Mehta A et al; on behalf of the FOS investigators. Fabry disease defined: baseline clinical manifestations of 366 patients in FOS – the Fabry Outcome Survey. Eur J Clin Invest 2004;34:236–42.
- Peters FPJ, Vermeulen A, Kho TL. Anderson-Fabry’s disease: α-galactosidase deficiency. Lancet 2001;357:138–40.
- Desnick RJ, Ioannou YA, Eng CM. α-Galactosidase A deficiency: Fabry disease. In: Scriver CR et al (eds) The Metabolic and Molecular Basis of Inherited Disease. 8th Edition, Vol. 3; McGraw Hill, New York 2001:3733–74.
- Schaeffer E, Gal A & Mehta A. Genotype and phenotype in Fabry disease: analysis of the Fabry Outcome Survey. Acta Paediatr Suppl 2005;94:87–92.
- Mehta A et al. Fabry disease: a review of current management strategies. QJM 2010;103(9):641–59.
- Mehta A et al. Fabry disease defined: baseline clinical manifestations of 366 patients in the Fabry Outcome Survey. Eur J Clin Invest 2004;34:236–42.
- MacDermot KD, Holmes A, Miners AH. Anderson-Fabry disease: clinical manifestations and impact of disease in a cohort of 60 obligate carrier females. J Med Genet 2001;38:769–75.
- Whybra C et al. Clinical manifestations in female Fabry disease patients. Contrib Nephrol 2001;136:245–50.
- Ries M et al. Enzyme replacement therapy with agalsidase alfa in children with Fabry disease. Pediatrics 2006;118:924–32.
- Tondel C et al. Renal biopsy findings in children with Fabry disease and minimal albuminuria. Am J Kidney Dis 2008;51:767–76.
- Marchesoni CL et al. Misdiagnosis in Fabry disease. J Pediatr 2010;156(5):828–31.
- Brady RO, Schiffmann R: Clinical features of, and recent advances in, therapy for Fabry disease. JAMA 2000;284:2771–5.
- Brouns R et al. Belgian Fabry study: prevalence of Fabry disease in a cohort of 1000 young patients with cerebrovascular disease. Stroke 2010;41(5):863–8
- Rolfs A et al. Acute cerebrovascular disease in the young: the Stroke in Young Fabry Patients study. Stroke 2013;44(2):340–9.
- El-Abassi R, Singhal D, England JD. Fabry’s disease. J Neurol Sci 2014;344:5–19.
- Whybra C et al. The Mainz Severity Score Index: a new instrument for quantifying the Anderson–Fabry disease phenotype, and the response of patients to enzyme replacement therapy. Clin Genet 2004;1–9.
- De Brabander I et al. Phenotypical characterization of α-galactosidase A gene mutations identified in a large Fabry disease screening program in stroke in the young. Clin Neurol Neurosurg 2013;115(7):1088–93.
- Schiffman R et al. Enzyme replacement therapy in Fabry disease: a randomised controlled trial. JAMA 2001;285:2743–9.
- Eng CM et al. Safety and efficacy of recombinant human α-galactosidase A replacement in Fabry disease. N Engl J Med 2001;345:9–16.
- Beck M et al. Fabry disease: overall effects of agalsidase alfa treatment. Eur J Clin Invest 2004;34:838–44.
- Pastores GM, Thadhani R. Advances in the management of Anderson-Fabry disease: enzyme replacement therapy. Expert Opin Biol Ther 2002;2:1–9.
- Hajioff D et al. Hearing loss in Fabry disease: the effect of agalsidase alfa replacement therapy. J Inher Metab Dis 2003;26:787–94.
- Weidemann F et al. Improvement of cardiac function during enzyme replacement therapy in patients with Fabry disease. A prospective strain rate imaging study. Circulation 2003;108:1299–301.
- Germain DP et al. Ten-year outcome of enzyme replacement therapy with agalsidase beta in patients with Fabry disease. J Med Genet 2015;52(5):353–8.
- Banikazemi M et al. Agalsidase-beta therapy for advanced Fabry disease: a randomized trial. Ann Intern Med 2007;146:77–86.
- Shiffman R et al. Four-year prospective clinical trial of agalsidase alfa in children with Fabry disease. J Pediatr 2010;156(5):832–7.
- Wraith JE et al. Safety and efficay of enzyme replacement therapy with agalsidase beta: an international, open-label study in pediatric patients with Fabry disease. J Pediatr 2008;152:563–70.
- Linthorst GE, Hollak CEM. Immune response to enzyme replacement therapy in Fabry disease: impact on clinical outcome? Mol Genet Metab 2008;96:1–3.
- Deegan PB. Fabry disease, enzyme replacement therapy and significance of antibody responses. J Inherit Metab Dis 2012;35:227–44.
- Whybra C et al. A 4-year study of the efficacy and tolerability of enzyme replacement therapy with agalsidase alfa in 36 women with Fabry disease. Genet Med 2009;11:441–9.
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- Hughes DA et al. Oral pharmacological chaperone migalastat compared with enzyme replacement therapy in Fabry disease: 18-month results from the randomised phase III ATTRACT study. J Med Genet 2016 Nov 10;pii: jmedgenet-2016-104178. doi: 10.1136/jmedgenet-2016-104178.
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